Abstract

Basic scientific and clinical translational progress in oncology has progressed at an exponential rate over the last 40 years. Much of this progress was germinated in the laboratory, where rigorous scientific dissection of the biological milieu that is neoplasia has been undertaken. Our basic understanding of cancer stems largely from interrogation of this very process, in human tissue samples. In Australia, tumour and tissue banks spawned in the latter half of the last century are now beginning to bear the fruit of scientific and translational discovery, as the critical mass required to definitively crystallise the biological and genetic principles of malignant proliferation has been achieved. This will only continue to be the case if clinicians and scientists alike continue their commitment to development and maintenance of high volume and high quality tissue banks.

Basic scientific and clinical translational progress in oncology has advanced at an exponential rate over the last 40 years. Much of this progress was germinated in the laboratory, where rigorous scientific dissection of the biological milieu that is neoplasia has been undertaken. During this time, we have seen parallel progress in information technology systems and mathematical modelling that facilitate experimentation without in vitro or in vivo tissue experimentation. However, our basic understanding of cancer stems largely from interrogation of cancer in human tissue samples. Tissue banks spawned in the latter half of the 20th century are now beginning to bear the fruit of scientific and translational discovery, as the critical mass required to definitively crystallise many of the biological and genetic principles of malignant proliferation have been achieved. This will only continue to be the case if clinicians and scientists alike continue their commitment to development and maintenance of high volume and high quality tissue banks.

Historical perspectives

In 1952, Rudolf Klen pioneered one of the first modern day tissue banks at the University Hospital Hradec Králové, Czech Republic.1 The conceptual framework upon which modern day banks operate still rely on the early principles championed by Klen. He originally characterised tissue banks as institutions that specialise “in the harvesting, processing, preservation, storage and distribution of various kinds of tissue for clinical and experimental practice”.1

While originally a repository for cadaver tissue, this bank slowly evolved to encompass living donor tissue for a number of purposes.2 The success of this institution, in both biomedical research and clinically related activities, stimulated interest in replication of this experience the world over. Today, tissue banks in various different forms exist in almost every clinical and/or research setting and have contributed unquestionably to our understanding of pathology and cancer in particular. Locally, for example, the Cancer Research Network of Sydney University now formally recognises nine separate tissue banks encompassing a range of neuroendocrine, head and neck, upper gastrointestinal, hepatopancreatobiliary, gynaeacological, breast, melanoma and paediatric malignancy.3 Similar tissue banks exist all over Australasia and have been responsible for innumerable published works of sufficient quality to attract ongoing support from the National Health and Medical Research Council.

The evolution of these banks has seen great change over the years. A ‘snatch and grab’, ‘good idea at the time’ mentality in the early years has given way to a highly structured and organised process of patient consent, tissue procurement, storage, preservation and access. The boom in our molecular understanding of disease has also forced us to think broadly regarding the ethical and moral responsibilities involved in storage of human tissue, issues that will continue to challenge all those involved in tissue banks and society at large forevermore.4

Translational relevance

Hansson, in his review of the quality of care and ethical issues involved in tissue banks and medical registries, cites the human papilloma virus vaccine as evidence of the translational impact of such resources.4 He argues that causality was only achieved in the laboratory setting, as a direct result of banked human tissue and prospectively collated clinical data that definitively proved the significance of human papilloma virus in cases of cervical cancer. Further experimentation ultimately led to the development of a vaccine that will unquestionably have a major impact on this disease for years to come.

There are innumerable examples that demonstrate the value of tissue banks. Within our own neuroendocrine tissue bank at the Kolling Institute of Medical Research, we have collected specimens with clinical data for close to 20 years. These samples have been fundamental in identifying biomarkers of diagnostic, prognostic and therapeutic significance, and have been the primary discovery tool for a number of molecular drivers in a multitude of endocrine malignancies.5,6 The tumour bank has also been an invaluable resource for stimulating international collaboration, especially within the realm of rare neuroendocrine malignancies that would otherwise suffer from a lack of cancer tissue critical mass. Cancer is an extremely heterogeneous disease,7 and tumour samples are an invaluable resource for demonstrating and documenting that heterogeneity in a real world setting. This fact alone sets tumour banks apart from cell lines and transgenic mouse models of disease as a key primary research tool.

The Clinical Oncological Society of Australia (COSA) has been fundamental to the development of tissue banks Australia wide. Particularly within the translational context of existing clinical trials conducted by the numerous Australia wide Cooperative Cancer Clinical Trial Groups (CCTGs), COSA has assisted in evolution of the Australasian Biospecimen Network (ABN-Oncology). This body serves as a unique local example of biobank cooperation and continues to attract National Health and Medical Research Council (NHMRC) funding. Under this arrangement, numerous biospecimen banks are linked, and among others, includes the Breast Cancer Biospecimen Resource, National Leukaemia and Lymphoma Tissue Bank, kConFab, Australian Prostate Cancer Collaboration BioResource, Australian Ovarian Cancer Study and Victorian Cancer Biobank. Previously, each of the CCTGs was responsible for collecting clinical samples for biospecimen processing under local policy, but this process was not consistent across banks. In 2008, a COSA initiated, national tissue banking workshop assisted in development of a standardised approach to sample collection, storage and access.8 This led to the development of consensus criteria relating to minimum clinicopathologic data elements, standardisation of consent/ethics, collection and storage of samples, as well as the distribution and sustainability of samples. The ABN-Oncology now serves as a consortium that seeks to centralise and link biospecimen resources in an effort to consolidate the strengths of each individual bank, thus providing “a conduit for researchers to gain access to ethically consented, high quality clinically-annotated biospecimens and data”.9

In an age of personalised medicine, tissue banks and the techniques that have developed through the investigation of cancer in associated laboratories are now becoming mainstream methods of diagnostics. In many ways, the bench and bedside are getting closer and closer together, not just physically with the development of translational cancer research hubs, but also metaphorically as scientific advances pave the way for future diagnostics and therapeutics.

The future

The ability to take full advantage of precious tissue bank resources into the future will require foresight. The informal ‘snatch and grab’ nature by which such banks originally evolved, is not appropriate for the 21st century climate where consent, confidentially and justification of research funding are at a premium.

As a means of maximising efficiency and protecting patient rights, tissue banks need a high degree of organisational structure and regulatory oversight. A recent review of the German experience highlights many of these themes and serves as a benchmark example of how tissue banks should be structured and managed with an emphasis on planning of service provision.10 While the audit cycle in the clinical setting is now a recognised means of quality assurance, uptake of this concept has been slow in tissue banks and repositories; not so in Germany however.

Based in Heidelberg, the National Centre of Tumour Diseases provided a total of 769 services over the six year audit period for 680 different research projects. Of these, 605 projects were successfully completed. The projects were composed of basic scientific research (73%), translational studies (22%) and epidemiological projects (3%). The centre facilitated the provision of formalin fixed, paraffin embedded tissue, fresh frozen tissue, tissue microarray based sections and immunohistochemical services. It was also able to track projects following provision of tissue and demonstrated that over 90% of projects were commenced following receipt of tissue by the primary investigator. Most projects were also pursued to completion with a high degree of investigator satisfaction (97%), reflecting the rigorous nature of tissue procurement, preservation and provision.

A prospective mindset is of the utmost importance in deriving clinically relevant information from tumour banks and clinical registries. Even within the realm of oncology, each malignant disease is a unique biological and clinical phenomenon that demands specific diagnostic and therapeutic strategies. The same could be said of tissue banks when it comes to handling related tissue and clinical data. As in the aforementioned German example, quality control should dictate the development of benchmark standards when it comes to tissue procurement and processing. More is needed however, and the Carmignani et al group eloquently describes a dedicated approach to banking prostate cancer samples.11 Beyond the collation of clinical data, this Italian group showed how it is possible to collate a complete biobank set of urine, blood, fresh cancer tissue and formalin fixed tissue. More specifically, they articulate how collection of high quality fresh cancer tissue requires an intimate knowledge of, and involvement in the biopsy procedure, with a standardised protocol for procurement of biobank tissue being undertaken in parallel with a clinical diagnostic procedure. This approach was highly successful in obtaining a complete set of biobank tissue without compromising clinical priorities and suggests that minimum world standards should be developed for each cancer type to ensure uniformity, maximise productivity and to serve as a guide for those developing new tissue banks.

Focused procurement of tissue bank specimens according to predefined standards has also been employed in mesothelioma.12 This example typifies many of the central themes that are now being promoted in an attempt to deliver consistency between biobanks, and translationally relevant information upon which scientific discovery can be pursued. Mohanty and colleagues describe, using mesothelioma as an example, how the development of a set of “international standards organisation” can be used to simplify and standardise the minimum dataset for each malignant disease based on data that is normally collated during a patient’s episode of care. A generic dataset is collated for each disease under the global headings of demographic, epidemiologic, anatomical pathology, genotype and treatment/outcomes. Specific fields then differentiate each cancer type from one another.

Locally, COSA and the ABN-Oncology have driven such initiatives within the context of clinical trials.8 This is encouraging, but more can be done to further enhance co-operation between tissue banks with a view to standardising the processes governing tissue handling, storage and provision. This will only be achieved if a sustainable health economic model is implemented and if all aspects and opportunities of cancer tissue processing are considered.

With regard to maximising opportunities, the role of the pathologist should not be forgotten; particularly given their role as the ultimate custodian of preserved human tissue samples. By their very nature, pathologists and pathology departments are uniquely positioned to participate in tissue banking. Tissue may not always be banked following biopsy or resection, but clinical specimens will always be sent to the pathologist for assessment. Until recently, the importance of pathology departments within the process of biospecimen procurement, storage and provision had not always been recognised, but this is changing. It is now acknowledged that pathology departments can only be engaged through appropriate funding, resource provision and scientific recognition. As such, COSA has developed a close alliance with the Royal Australasian College of Pathologists (RCPA) to assist in this regard. As an example, COSA and the RCPA have previously collaborated to lobby government in pursuit of a Medicare item number for preparation of specimens for the purposes of research.8 It makes sense to harness not only the pathologist’s access to tissue, but also their knowledge and skills within the context of malignant disease. The value of pathology support to tissue banking cannot be overstated.

These initiatives highlight the underrated importance of clinician leadership in successful execution of such an endeavour, from patient consent, to tissue bank derived scientific discovery. All too often, in today’s busy clinical environment, tissue banking is an afterthought that is seen as an obstacle to completion of clinical duties, whereby tissue harvesting is frequently attended to by inexperienced or unaccustomed personnel. It is no surprise that disappointing laboratory results often accompany such an approach. In this day and age, it could be argued that a checkbox for tissue banking should be added to the widely adopted ‘Time Out’ surgical safety checklist that is carried out before every procedure.13 The 2008 COSA workshop on tissue banking for cancer clinical trials also raised the possibility of imposing an opt-out approach to tissue donation at the time of each cancer diagnosis.8

Biological informatics

The boom in bioinformatic information now accompanying banked tissue specimens is also a concern and requires a specific effort to manage this data. Recent whole genome sequencing studies, based entirely upon tissue specimens, are a prime example of the sheer volume of data that must be handled. Coalescing the molecular and genetic data that are generated from these studies with clinical data to derive translational relevance is a difficult task and requires specific bioinformatic expertise. Several groups are now developing software solutions to meet these evolving challenges.14

The whole genome sequencing experience has fast-tracked an issue that has plagued tissue banks since their inception. Linking tissue samples with clinical data has long been a difficult task and one that is now of great translational importance. The development of biomarkers in particular, mandates knowledge regarding patient demographics, diagnostics, the treatment employed and clinical outcome. Traditionally, tissue bank repositories acted as tissue storehouses and linking clinical data was a distinct task in its own right. However, there is now an increasing recognition of the need to link clinical data, a task that significantly increases the organisational and ethical burden upon such organisations.14 It has also been recognised that hospital based medical records fail to capture the necessary data to best take advantage of potential translational project initiatives.15 This data is often collated retrospectively and is invariably incomplete. However, with the local advent of translational cancer research hubs throughout Australia, and more specifically, the instigation of specific projects geared toward linking various forms of tissue/clinical data (eg.the CHeReL inititaive),16 these issues are being managed proactively. The increasing uptake of electronic medical records also assists in this regard and is of particular interest in a country like Australia, where the largely dispersed nature of our population makes the study of rarer diseases particularly challenging. International collaboration is also greatly facilitated with such infrastructure in place.

Such an approach requires a high degree of organisational and cross-institutional co-operation. Success is also dependent on developing the necessary infrastructure, and recruiting personnel with an appropriate skill set to manage all aspects of the bank, from tissue handling, to ethics reviews, database management, clinician engagement and patient consent. Legal, ethical and data protection assurance practices should not be neglected. It should also be borne in mind that none of this is possible without adequate funding.

Conclusion – a call to arms

Our current understanding of tumour biology would not have been possible without the access to human tissue that tumour and tissue banks provide for medical research purposes. In the current age of true translational, bench to bedside scientific and clinical progress, tissue banks need to be promoted in a specific effort to ensure that funding is continued, regulatory oversight is maintained (but not obstructive), ethical principles are upheld and clinicians are engaged. These banks will increasingly take advantage of progress in information technology systems and molecular techniques. Above all else, those at the forefront of clinical care must realise the privileged nature of clinical contact with patients. They must continue promoting tissue bank submissions to ultimately assist in completion of the translational progress cycle, from the bedside, to the bench, and then back to the patient again, where it counts.